L Panach1, E Serna1, J J Tarín2, A Cano3, M Á García-Pérez4,5. 1. Research Unit - Institute of Health Research INCLIVA, Av. Menéndez Pelayo, 4 accesorio, 46010, Valencia, Spain. 2. Department of Cellular Biology, Functional Biology and Physical Anthropology, University of Valencia, Valencia, Spain. 3. Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Valencia, Spain. 4. Research Unit - Institute of Health Research INCLIVA, Av. Menéndez Pelayo, 4 accesorio, 46010, Valencia, Spain. migarpe@uv.es. 5. Department of Genetics, University of Valencia, Burjassot, Spain. migarpe@uv.es.
Abstract
This study represented a translational study that first compared gene expression of B cells of BM from ovariectomized and control mice, and then analyzed some of the differentially expressed genes in women. Results showed novel genetic associations with bone phenotypes and points to the CD80 gene as relevant in postmenopausal bone loss. INTRODUCTION: Osteoporosis is a multifactorial disease with a strong genetic component. However, to date, research into osteoporosis has only been able to explain a small part of its heritability. Moreover, several components of the immune system are involved in the regulation of bone metabolism. Among them, B cells occupy a prominent place. METHODS: The study consisted of two stages. In the first, gene expression in bone marrow B cells is compared between ovariectomized and SHAM control mice using microarrays. In the second, we studied the association of polymorphisms in some differentially expressed genes (DEG) in a cohort of postmenopausal women. RESULTS: The present study has found 2791 DEG (false discovery rate (FDR) <5%), of which 1569 genes were upregulated (56.2%) and 1122 genes (43.8%) were downregulated. Among the most altered pathways were inflammation, interleukin signaling, B cell activation, TGF-beta signaling, oxidative stress response, and Wnt-signaling. Sixteen DEG were validated by MALDI-TOF mass spectrometry or qPCR. The translational stage of the study genotyped nine single nucleotide polymorphisms (SNPs) of DEG or related and detected association with bone mineral density (BMD) (nominal P values), while adjusting for confounders, for SNPs in the CD80, CD86, and HDAC5 genes. In the logistic regression analysis adjusted for confounders, in addition to the SNPs in the aforementioned genes, the SNPs in the MMP9 and SOX4 genes were associated with an increased risk of osteoporosis. Finally, two SNPs (in the CD80 and SOX6 genes) were associated with an increased risk of bone fragility fracture (FF). However, after Bonferroni correction for multiple testing, only the association between CD80 with BMD and risk of osteoporosis remained significant. CONCLUSION: These results show that the use of animal models is an appropriate method for identifying genes associated with human bone phenotypes.
This study represented a translational study that first compared gene expression of B cells of BM from ovariectomized and control mice, and then analyzed some of the differentially expressed genes in women. Results showed novel genetic associations with bone phenotypes and points to the CD80 gene as relevant in postmenopausal bone loss. INTRODUCTION:Osteoporosis is a multifactorial disease with a strong genetic component. However, to date, research into osteoporosis has only been able to explain a small part of its heritability. Moreover, several components of the immune system are involved in the regulation of bone metabolism. Among them, B cells occupy a prominent place. METHODS: The study consisted of two stages. In the first, gene expression in bone marrow B cells is compared between ovariectomized and SHAM control mice using microarrays. In the second, we studied the association of polymorphisms in some differentially expressed genes (DEG) in a cohort of postmenopausal women. RESULTS: The present study has found 2791 DEG (false discovery rate (FDR) <5%), of which 1569 genes were upregulated (56.2%) and 1122 genes (43.8%) were downregulated. Among the most altered pathways were inflammation, interleukin signaling, B cell activation, TGF-beta signaling, oxidative stress response, and Wnt-signaling. Sixteen DEG were validated by MALDI-TOF mass spectrometry or qPCR. The translational stage of the study genotyped nine single nucleotide polymorphisms (SNPs) of DEG or related and detected association with bone mineral density (BMD) (nominal P values), while adjusting for confounders, for SNPs in the CD80, CD86, and HDAC5 genes. In the logistic regression analysis adjusted for confounders, in addition to the SNPs in the aforementioned genes, the SNPs in the MMP9 and SOX4 genes were associated with an increased risk of osteoporosis. Finally, two SNPs (in the CD80 and SOX6 genes) were associated with an increased risk of bone fragility fracture (FF). However, after Bonferroni correction for multiple testing, only the association between CD80 with BMD and risk of osteoporosis remained significant. CONCLUSION: These results show that the use of animal models is an appropriate method for identifying genes associated with human bone phenotypes.
Entities:
Keywords:
Association studies; B cells; Osteoporosis; Ovariectomy; Translational research
Authors: M A García-Pérez; R Del Val; I Noguera; C Hermenegildo; B Pineda; A Martinez-Romero; A Cano Journal: Int J Immunopathol Pharmacol Date: 2006 Oct-Dec Impact factor: 3.219
Authors: Antonio-Jorge Cano-Marquina; Miguel-Ángel García-Pérez; Juan J Tarín; Alicia M Maceira; Juan Cosín-Sales; Antonio Cano Journal: Medicine (Baltimore) Date: 2021-06-11 Impact factor: 1.817